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Published in: International Orthopaedics 12/2014

01-12-2014 | Original Paper

A pilot study investigating the histology and growth factor content of human non-union tissue

Authors: Philipp Schwabe, Paul Simon, Zienab Kronbach, Gerhard Schmidmaier, Britt Wildemann

Published in: International Orthopaedics | Issue 12/2014

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Abstract

Purpose

The reason for the formation of an atrophic non-union is not clear and an altered vascularization as well as a deregulation of endogenous growth factors is hypothesized. To obtain more information, we analysed human non-union tissue regarding the histology and quantity of several growth factors.

Methods

Tissue from patients with an atrophic non-union (n = 44) or with a healed fracture (n = 13) was analysed. Using histological and immunohistochemical methods the tissue composition was investigated. On the protein level the amount of several growth factors important for bone healing was analysed.

Results

The tissue composition was very inhomogeneous containing fibrous, cartilaginous and bony tissue. Vessels were present in all investigated samples without a difference between the tissue from non-union and control patients. The growth factor BMP-2 was below the detection limit in all samples, whereas IL-6 and IGF-I were measured only in a few samples of both groups. TGF-ß1, VEGF-A and BMP-4 were detectable in the majority of the samples of both groups with a high variability in the amount but no difference between the groups. The quantity of both growth factors, BMP-7 and PDGF-AB, was significantly lower in the non-union tissue compared to the healed controls.

Conclusion

The reduced quantity of BMP-7 and PDGF-AB might be responsible for the impaired healing. Further studies analysing material from more patients and investigating the early healing phases, however, are necessary to obtain further information and consequently improve healing strategies.
Literature
1.
go back to reference Giannoudis PV, Einhorn TA, Schmidmaier G, Marsh D (2008) The diamond concept—open questions. Injury 39(Suppl 2):S5–S8PubMedCrossRef Giannoudis PV, Einhorn TA, Schmidmaier G, Marsh D (2008) The diamond concept—open questions. Injury 39(Suppl 2):S5–S8PubMedCrossRef
2.
go back to reference Ferguson C, Alpern E, Miclau T, Helms JA (1999) Does adult fracture repair recapitulate embryonic skeletal formation? Mech Dev 87:57–66PubMedCrossRef Ferguson C, Alpern E, Miclau T, Helms JA (1999) Does adult fracture repair recapitulate embryonic skeletal formation? Mech Dev 87:57–66PubMedCrossRef
3.
go back to reference Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA (2008) Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 87:107–118PubMedCentralPubMedCrossRef Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA (2008) Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 87:107–118PubMedCentralPubMedCrossRef
4.
go back to reference Kon T, Cho TJ, Aizawa T, Yamazaki M, Nooh N, Graves D et al (2001) Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res 16:1004–1014PubMedCrossRef Kon T, Cho TJ, Aizawa T, Yamazaki M, Nooh N, Graves D et al (2001) Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res 16:1004–1014PubMedCrossRef
5.
go back to reference Ruschke K, Hiepen C, Becker J, Knaus P (2012) BMPs are mediators in tissue crosstalk of the regenerating musculoskeletal system. Cell Tissue Res 347:521–544PubMedCrossRef Ruschke K, Hiepen C, Becker J, Knaus P (2012) BMPs are mediators in tissue crosstalk of the regenerating musculoskeletal system. Cell Tissue Res 347:521–544PubMedCrossRef
6.
go back to reference David L, Feige JJ, Bailly S (2009) Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine Growth Factor Rev 20:203–212PubMedCrossRef David L, Feige JJ, Bailly S (2009) Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine Growth Factor Rev 20:203–212PubMedCrossRef
7.
go back to reference Wildemann B, Kadow-Romacker A, Haas NP, Schmidmaier G (2007) Quantification of various growth factors in different demineralized bone matrix preparations. J Biomed Mater Res 81:437–442CrossRef Wildemann B, Kadow-Romacker A, Haas NP, Schmidmaier G (2007) Quantification of various growth factors in different demineralized bone matrix preparations. J Biomed Mater Res 81:437–442CrossRef
8.
go back to reference Garcia P, Histing T, Holstein JH, Klein M, Laschke MW, Matthys R et al (2013) Rodent animal models of delayed bone healing and non-union formation: a comprehensive review. Eur Cell Mater 26:1–12PubMed Garcia P, Histing T, Holstein JH, Klein M, Laschke MW, Matthys R et al (2013) Rodent animal models of delayed bone healing and non-union formation: a comprehensive review. Eur Cell Mater 26:1–12PubMed
9.
go back to reference Kokubu T, Hak DJ, Hazelwood SJ, Reddi AH (2003) Development of an atrophic nonunion model and comparison to a closed healing fracture in rat femur. J Orthop Res 21:503–510PubMedCrossRef Kokubu T, Hak DJ, Hazelwood SJ, Reddi AH (2003) Development of an atrophic nonunion model and comparison to a closed healing fracture in rat femur. J Orthop Res 21:503–510PubMedCrossRef
10.
go back to reference Kloen P, Lauzier D, Hamdy RC (2012) Co-expression of BMPs and BMP-inhibitors in human fractures and non-unions. Bone 51:59–68PubMedCrossRef Kloen P, Lauzier D, Hamdy RC (2012) Co-expression of BMPs and BMP-inhibitors in human fractures and non-unions. Bone 51:59–68PubMedCrossRef
11.
go back to reference Fajardo M, Liu CJ, Egol K (2009) Levels of expression for BMP-7 and several BMP antagonists may play an integral role in a fracture nonunion: a pilot study. Clin Orthop Relat Res 467:3071–3078PubMedCentralPubMedCrossRef Fajardo M, Liu CJ, Egol K (2009) Levels of expression for BMP-7 and several BMP antagonists may play an integral role in a fracture nonunion: a pilot study. Clin Orthop Relat Res 467:3071–3078PubMedCentralPubMedCrossRef
12.
go back to reference Kwong FN, Hoyland JA, Freemont AJ, Evans CH (2009) Altered relative expression of BMPs and BMP inhibitors in cartilaginous areas of human fractures progressing towards nonunion. J Orthop Res 27:752–757PubMedCrossRef Kwong FN, Hoyland JA, Freemont AJ, Evans CH (2009) Altered relative expression of BMPs and BMP inhibitors in cartilaginous areas of human fractures progressing towards nonunion. J Orthop Res 27:752–757PubMedCrossRef
13.
go back to reference Kloen P, Doty SB, Gordon E, Rubel IF, Goumans MJ, Helfet DL (2002) Expression and activation of the BMP-signaling components in human fracture nonunions. J Bone Joint Surg Am 84-A:1909–1918PubMed Kloen P, Doty SB, Gordon E, Rubel IF, Goumans MJ, Helfet DL (2002) Expression and activation of the BMP-signaling components in human fracture nonunions. J Bone Joint Surg Am 84-A:1909–1918PubMed
14.
go back to reference Niikura T, Hak DJ, Reddi AH (2006) Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures. J Orthop Res 24:1463–1471PubMedCrossRef Niikura T, Hak DJ, Reddi AH (2006) Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures. J Orthop Res 24:1463–1471PubMedCrossRef
15.
go back to reference Andrew J, Hoyland J, Freemont A, Marsh D (1995) Platelet-derived growth factor expression in normally healing human fractures. Bone 16:455–460PubMed Andrew J, Hoyland J, Freemont A, Marsh D (1995) Platelet-derived growth factor expression in normally healing human fractures. Bone 16:455–460PubMed
16.
go back to reference Beer HD, Longaker MT, Werner S (1997) Reduced expression of PDGF and PDGF receptors during impaired wound healing. J Invest Dermatol 109:132–138PubMedCrossRef Beer HD, Longaker MT, Werner S (1997) Reduced expression of PDGF and PDGF receptors during impaired wound healing. J Invest Dermatol 109:132–138PubMedCrossRef
17.
go back to reference Zeckey C, Hildebrand F, Glaubitz LM, Jurgens S, Ludwig T, Andruszkow H et al (2011) Are polymorphisms of molecules involved in bone healing correlated to aseptic femoral and tibial shaft non-unions? J Orthop Res 29:1724–1731PubMedCrossRef Zeckey C, Hildebrand F, Glaubitz LM, Jurgens S, Ludwig T, Andruszkow H et al (2011) Are polymorphisms of molecules involved in bone healing correlated to aseptic femoral and tibial shaft non-unions? J Orthop Res 29:1724–1731PubMedCrossRef
18.
go back to reference Wildemann B, Kadow-Romacker A, Pruss A, Haas NP, Schmidmaier G (2007) Quantification of growth factors in allogenic bone grafts extracted with three different methods. Cell Tissue Bank 8:107–114PubMedCentralPubMedCrossRef Wildemann B, Kadow-Romacker A, Pruss A, Haas NP, Schmidmaier G (2007) Quantification of growth factors in allogenic bone grafts extracted with three different methods. Cell Tissue Bank 8:107–114PubMedCentralPubMedCrossRef
19.
go back to reference Vukicevic S, Oppermann H, Verbanac D, Jankolija M, Popek I, Curak J et al (2014) The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing. Int Orthop 38:635–647PubMedCrossRef Vukicevic S, Oppermann H, Verbanac D, Jankolija M, Popek I, Curak J et al (2014) The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing. Int Orthop 38:635–647PubMedCrossRef
Metadata
Title
A pilot study investigating the histology and growth factor content of human non-union tissue
Authors
Philipp Schwabe
Paul Simon
Zienab Kronbach
Gerhard Schmidmaier
Britt Wildemann
Publication date
01-12-2014
Publisher
Springer Berlin Heidelberg
Published in
International Orthopaedics / Issue 12/2014
Print ISSN: 0341-2695
Electronic ISSN: 1432-5195
DOI
https://doi.org/10.1007/s00264-014-2496-6

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